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161 Cards in this Set
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Antigen
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foreign substances that induce specific immune responses. Origin of term “antibody generating”
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Clone
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the progeny of a single receptor-expressing cell that expands upon stimulation with antigen
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Vaccine
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a component of the pathogen (or closely related pathogen) that can be used to induce specific immunity by inducing immunological memory
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Lymphoid organs
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where important developmental and immunological events take place
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Bone Marrow
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contains stem cells from which all lymphocytes derive and is an important site for differentiation of antibody producing lymphocytes (B-lymphocytes)
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Thymus
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induces the differentiation of immature cells into an important subset of lymphocytes with regulatory and effector functions called T-lymphocytes
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Spleen and lymph nodes
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sites where lymphocytes and dendritic cells interact with each other to initiate immune responses
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Humoral Response
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Antibodies secreted by B cells
Recognizes 3 dimensional molecular shapes Neutralizes bacteria, free viruses, and toxins |
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Cellular Response
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T cells
Recognizes peptides of foreign proteins within cells Neutralizes cancers, viruses, and mutations |
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Helper T cell
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Express CD4
Recognize antigens on the surfaces of APCs and secrete cytokines, which stimulate different mechanisms of immunity and inflammation |
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Cytotoxic T cell (CTL)
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Express CD8
Recognize antigens on infected cells and kill these cells |
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Regulatory T cells
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Suppress and prevent immune response (e.g. to self antigens)
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NK cells
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Use receptors with more limited diversity than T or B cell antigen receptors to recognize and kill their targets, such as cells infected with certain viruses
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B lymphocytes
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Make antibodies that prevent and eliminate infections by extracellular microbes
Can develop into antibody-secreting plasma cells Has a B cell receptor for antigen that is a membrane bound antibody (just like the ones they secrete) Recognize soluble antigens |
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T lymphocytes (in general)
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Mediate cellular effector functions and are the principal regulatory cells of the immune system
Has a T cell receptor for antigen that is structurally related to immunoglobulin, never releases their receptor, can only see what is on the surface of other cells |
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Role of innate immune system
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Identify pathogen breach
Maintain continuous surveillance of all areas |
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Common myeloid progenitor cell
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stem cell from which all circulating cells of the immune system are generated. Differentiates into B, T, and NK cells, all granulocytes, monocytes, erythrocytes, and platelets
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How do lymphocytes enter stroma of lymph nodes?
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Through artery in the hilum which leads to post capillary venules (HEVs)
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What types of cells are found in the paracortical area of lymph nodes?
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T cells
Macrophages Dendritic cells |
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Where do B cells accumulate in lymph nodes and how do they get there?
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B cell zones
germinal centers Attracted by cytokines and chemokines |
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What cells enter lymph nodes through afferent lymphatics?
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Dendritic cells, Macrophages
Free antigen |
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What cells enter lymph nodes through HEVs and how?
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T cells
B cells Lymphocytes express selectins which bind to distinct molecules on HEV |
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Unique morphology of spleen
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Has no afferent lymphatics or HEVs
Lymphocytes enter the stroma through the leaky circulation under the shear stress of the flow |
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White pulp
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lymphoid tissue: includes T cell and B cell zones
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Red pulp
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composed of vascular sinusoids filled with RBC’s, macrophages, and dendritic cells
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Cellular components of the cutaneous immune system: Epidermis
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Keratinocytes
Intraepidermal lymphocytes Langerhans cells—take up bacteria or pathogens and move into the lymphatics and then the lymph nodes. 2,000/mm^2 of skin |
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Cellular components of the cutaneous immune system: Dermis
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Dermis
T lymphocytes Macrophages Dendritic cells—take up bacteria or pathogens and move into the lymphatics and then the lymph nodes |
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Components of the mucosal immune system
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Peyer’s patches:
Mainly B cells which make IgA antibodies, which clear bacterial infections in gut M cells lie above them and internalize antigens, which are delivered into the Peyer’s patches Intraepithelial collections of T-cells (found in villi) Both drain into lymphatics |
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Lamina propria
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layer of tissue directly under epithelial cells of intestines. Location of Peyer's patches
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What happens when a resident macrophage responds to a microbial invasion?
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Macrophage produces TNF and IL-1 (cytokines)
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What do TNF and IL-1 do?
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that act on epithelial cells lining small blood vessels and lymphatics, causing them to increase expression of adhesion molecules in order to attract undifferentiated monocytes and neutrophils to area of infection
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Where do naive T cells migrate to and how/why?
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HEVs
HEVs have L-selectin ligand which binds to L-selectin on T cells CCL19, and CCL21 (binding chemokines) also displayed on surface of HEV and attract naive T cells |
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Where do activated T cells migrate to and how/why?
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Leave lymph nodes via efferent lymphatics and find their way into thoracic duct and circulation
Home to site of infection in peripheral tissues via E and P selectins and integrins, chemokines produced at site of infection |
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Components of the innate immune system
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o Epithelial barriers
o Phagocytes/granulocytic/monocytes o Complement o NK cells |
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Components of the adaptive immune system
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o B lymphocytes (plasma cells, memory cells)
o Antibodies o T lymphocytes (Effector T cells) Also macrophages and dendritic cells (activation of T cells) |
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CD3
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marker found on all T cells
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CD4
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marker found on helper T cells
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CD8
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marker found on cytotoxic T cells
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CD19
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marker found on B cells
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Primary follicles in lymph nodes:
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Do not have a germinal center
Contain B cells that have not: seen antigen undergone somatic hypermutation undergone class switch recombination |
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Secondary follicles in lymph nodes:
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Have germinal centers
contain B cells that have seen antigen are undergoing (or have undergone) somatic hypermutation and class switch recombination |
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MALT
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Mucosa Associated Lymphoid tissue. Includes BALT (Bronchioles...) and GALT (gastrointestinal...)
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protects mucosal surfaces, namely respiratory and GI tracts. Includes peyer's patches and intraepithelial lymphocytes
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Neutrophils
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Also called polymorphonuclear leukocyte (PMN)
Most abundant circulating WBC most important component in killing bacteria and fungi short life (1/2 life is about 6 hrs) Phagocytosis and killing of microorganisms Attracted by complement fragment C5a |
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Eosinophils
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play a role in allergic reactions and helminthic infections
beneficial effect remains unclear killing of antibody-coated parasites through release of granule contents |
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Basophils
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hypersensitivity/allergic reactions (histamine, serotonin in granules)
controls inflammatory response to parasites |
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Plasma cell
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fully differentiated form of B cell that secretes antibodies
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Mast cell
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expulsion of parasites from body through release of granules containing histamine and other active agents
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B7
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Expressed by macrophages, dendritic cells, and B cells after they have been activated by binding bacterial or pathogenic structures
interacts with CD28 on T cells |
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Activation of dendritic cell
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Cell either binds/engulfs a pathogenic structure or has it's toll-like receptor stimulated
If structure is engulfed, it is broken down and displayed on MHC molecules The cell expesses B7, needed to activate T cells |
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Role of Epithelia in immune response
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Act as physical barrier to infection
kill microbes by locally producing antibiotics (definsins) Harbor intraepithelial lymphocytes |
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intraepithelial lymphocytes
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recognize bacterial lipids instead of peptide antigens
kill microbes and infected cells |
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Role of cytokines in innate immunity
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produced by macrophages and NK cells
mediate the early neutrophil-dominated inflammatory reactions to microbes and promote elimination of microbes |
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role of cytokines in adaptive immunity
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stimulate proliferation and differentiation of antigen-stimulated lymphocytes and activate specialized effector cells
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Role of IFN gamma in innate immunity
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secreted by NK cells, tell macrophages to work better
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Role of IFN gamma in adaptive immunity
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secreted by helper T cells
activate macrophages Cause B cells to secrete antibody, isotype switch cause CTL differentiation |
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Role of IL-12
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secreted by macrophages
encourages NK cells to secrete more IFN gamma |
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Injury response
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Distruption of cells causes mast cells degranulate, release histamine
Complement is activated, some parts (C5a) act as chemoattractants, others bind to bacteria blood flow and leakiness increased Tissue macrophages phagocytose bacteria and then secrete cytokines, attracting neutrophils and blood-borne moncytes to the area |
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Acute inflammation response
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vasodilation, increasing blood flow causing rubor and calor (redness and warmth)
increased permeability of vasculature, causing tumor or swelling fluid loss leading to concentration of RBCs and slowed blood flow (stasis) emigration of leukocytes from microcirculation due to stasis and activation, also contributing to tumor |
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Role of monocytes in immune response
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they differentiate into macrophages and phagocytose infectious organisms such as bacteria, fungi, or parasites, especially if the pathogens have been covered with antibodies or complement
persist and can undergo futher cell division at an inflammatory site, providing for a persistent response produce cytokines that recruit other cells |
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Mac-1 integrin
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Receptor on phagocyte
Binds microbes opsonized with complement proteins |
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phagocytosis and intracellular destruction of microbes (process)
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microbe is bound to receptor
microbe is internalized into phagosome phagosome fuses with lysosome to form phagolysosome mictobes are killed by ROS, NO intermediates, and proteolytic enzymes |
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mannose receptor
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receptor on phagocyte
binds to mannose on microbe, which is not present on human cells, and causes microbe to be internalized by phagocyte |
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chronic granulomatous disease
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people lack phagocytic oxidases so don't generate enough ROS
causes susceptability to catalase + microorganisms (e.g. staph) since they can deactivate small levels of ROS could be x-linked or autorecessive causes chronic pus-forming abcesses |
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Types of receptors on macrophage
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mannose receptor
scavenger receptor toll receptor Mac-1 integrin |
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NK cells
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don't require stimulation to kill infected or transformed cells
killing done with perforin or by antibody dependent cytotoxicity large granular lymphocytes |
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antibody-dependent cell-mediated cytotoxicity
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Antibodies of certain IgG subclasses bind to cells
Fc regions of antibodies are recognized by Fc gamma receptor on NK cells NK cells are activated and kill the cell |
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Killing of helminth by eosinophil
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IgE antibodies bind to helminthic parasites
Fc regions of antibodies are recognized by Fc epsilon receptors on eosinophils eosinophils ar activated to release their granule contents, which kill the parasites |
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perforin/granzyme
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released by NK cells into infected cell
causes cell death in target cell |
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How does an NK cell know which cells to kill?
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NK cells do not efficiently kill class 1 MHC-expressing targets (should be all normal cells) because it is recognized by an inhibitory receptor on the NK cell
if a virus infection inhibits class 1 MHC expression on a cell, the NK cell inhibitory receptor is not engaged and the NK cell kills the infected cell |
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Toll-like receptors (TLRs)
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serve as pattern recognition receptors for a family of microbes
bind to PAMPs (pathogen associated molecular patterns) Can recognize LPS found on or in macrophages, dendritic cells, neutrophils, mucosal epithelial cells, and endothelial cells When engaged they activate the cell they are on |
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clinical signs of an inflammatory response
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redness-rubor
heat-calor swelling-tumor pain-dolor loss of function-functio laesa |
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3 pathways of complement activation
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classical pathway--triggered by antibodies that bind pathogens
alternative pathway (most important)--antibody-independent pathway in which complement activation is amplified on microbial surfaces mannose binding lectin (MBL) pathway--also antibody-independent that recognizes a microbial surface feature |
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complement
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multi component host defense system
consists of more than 35 proeins that participate in a highly regulated fashion provide many of the effector functions of humoral immunity and inflammation |
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effects of complement
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can cause pathogen lysis by forming holes or pores in their membranes
can also cause damage to infected cells |
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how human cells avoid complement attack
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inhibitor proteins found on human cell surfaces
in the absence of such complement regulators, human diseases arise |
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3 major functions of complement
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1. opsonizes microbe with C3b (or C4b), which promotes phagocytosis of microbe
2. stimulation of inflammatory reactions by recruitment and activation of leukocytes by C5a and stimulation of mast cells/granulocytes by C3a, C4a, and C5a 3. Complement mediated cytolysis by formation of membrane attack complex, a transmembrane channel in the lipid bilayer of the cell, causing osmotic lysis of microbe |
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C3b receptor
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found on macrophages, binds to C3b that is opsonizing outside of microbe, causes macrophage to phagocytose microbe
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Classical pathway
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C1 binds to 2 or more Fc portions of antigen bound IgM or IgG
C4 and then C2 bind to the Ig associated C1q, forming the C3 convertase C3 is fragmented to C3a and b C3b binds to convertase creating the C5 convertase C5 is fragmented, and C5b binds to cell surface C6, 7, 8, and a cohort of C9s bind to form the MAC, putting a hole in the cell |
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CR1
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complement receptor on erythrocytes that binds opsonized antigen-antibody complexes. Erythrocyte brings complex to the spleen or liver, where it is cleared by phagocytic cells
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4th function of complement
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increases B cell responses to antigens
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Classical pathway order
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C1 C4 C2 C3 C5 C6 C7 C8 C9
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Alternative pathway
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C3 is spontaneously cleaved and C3b deposits on the surface of a microbe
factor B binds to C3b forming the alternative pathway C3 convertase, stabilized by properain C3 is cleaved to produce more C3b, which binds to the convertase making a C5 convertase The rest proceed exactly like classical pathway |
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MBL pathway
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mannan-binding lectin binds mannose on pathogen surface and activates C4 directly, bypassing C1
the rest of the pathway is exactly like the classical pathway |
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Ways to regulate complement activity
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1. C1INH inhibits C1 activation by displacing C1r2s2 from C1q
2. proteins that inhibit the converases (DAF and Factor 1) 3. Proteins inhibit the MAC (CD59 and S protein) most important one |
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angioneurotic edema
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associated with inherited deficiency in C1 INH, so fails to inhibit classical complement pathway, leads to edema
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paroxysmal nocturnal hemoglobinuria
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caused by absence of functional DAF on erythrocytes, can't inhibit C3 convertase
marked by passing blood in urine at night, seen in young adults |
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protectin (CD59) deficiency
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can't regulate the formation of MAC
leads to hemolytic anemia and hemorrhagic strokes extremely rare |
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roles of antibodies
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neutralization of microbes and toxins
opsonization and phagocytosis of microbes antibody dependent cellular cytotoxicity (NK cells, eosinophils) complement activation and therefore lysis of microbes, phagocytosis of microbes opsonized with complement, and inflammation |
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B cell maturation phases
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1. Pro-B cell--heavy chain D-J then V-DJ rearranging
2. Pre-B cell--light chain V-J rearranging 3. Immature B cell--IgM expressed on cell surface |
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Checkpoints in lymphocyte maturation
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Pro-B/T cell stage: failure to express pre-antigen receptor--apoptosis
Pre-B/T cell stage--failure to express antigen receptor--apoptosis Immature B/T cell stage Strong antigen recognition--negative selection and either apoptosis or receptor editing (B cell, first time) Weak antigen recognition--positive selection |
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central tolerance
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Immature B cells that encounter self antigens in the bone marrow die by apoptosis (clonal deletion) or change the specificity of their antigen receptors by undergoing further antibody gene rearrangement (receptor editing)
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Peripheral tolerance
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B cells that incounter self antigens in peripheral tissues become unresponsive (anergic), are excluded from lymphoid follicles, or die by apoptosis
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B cell activation
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2 signals required
1. Ig crosslinking of antibody molecule on B cell surface 2. T cell "help" or co-stimulation of CD40 by CD40L immature B cells undergo apoptosis if they only receive signal 1. However, mature B cells will become activated if they see signal 1 |
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effect of crosslinking Ig receptors of B cells by antigen
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triggers biochemical signals that are transduced by the Ig associated proteins Ig alpha and Ig beta
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germinal center
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specialized microenvironment in the lymph node in which B cell proliferation, somatic hypermutation, and selection for antigen binding occur. More immature cells are in the center, as they mature they move outwards
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Fab
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fragment antigen binding, comprised of the antibody V (variable) region
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CDR
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Complementarity determining regions
hypervariable sequences in the V-region that bind antigen make most contacts with antigen |
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Why are antibody molecules flexible?
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There are hinge regions located between the Ch1 and Ch2 domains on the heavy chain, which permit independent movement of antigen-binding sites relative to the rest of the molecule
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nature of antigenic determinants
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antibody binding to antigen may depend on protein folding and/or primary structure of the antigen
-some determinants are accessible in native proteins and are lost on denaturation -some determinants are only accessible upon denaturation -some determinants can be seen either way |
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Avidity vs affinity
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Avidity refers to the sum total of antigen binding at all of the antigen binding sites
Affinity refers to the strength of the binding at a single binding site |
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How many antigen-binding sites does secreted IgM have?
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10
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How many antigen-binding sites does secreted IgG have?
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2
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Immune complexes
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antigen-antibody complexes
Bigger when ratios of antigen to antibody is in zone of equivalence. Easier to clear from body Smaller complexes form when ratios are off. these are hard to clear and often lodge in joints or kidneys |
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affinity maturation
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mutations in the V region of antibody lead to changes in fine specificity without changes in C region-dependent effector functions
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Isotype switching
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C regions of antibodies change without changes in the antigen-binding V region. Seen in both membrane-bound and secreted antibodies
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consequences of somatic mutation of Ig genes
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1. apoptosis due to loss of functional receptor
2. autoreactivity 3. affinity maturation (when coupled with SELECTION for antigen binding) |
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Antibody Heavy Chain Isotypes
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IgM, IgG, IgA, IgE
All start off as IgM, then others are generated by site-directed DNA recombination between switch regions in introns between heavy chain constant region genes certain cytokines induce or inhibit the production of specific isotypes IgD also exists |
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IgA
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functions in mucosal immunity
Secreted form is usually a dimer (but can be monomer or trimer) |
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IgD
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Naive B cell antigen receptor, can be coexpressed with IgM in some cases
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IgE
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Defense agains helminthic parasites, found in skin
immediate hypersensitivity Has long constant region secreted as monomer |
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IgG
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opsonization, complement activation, antibody dependent cell-mediated cytotoxicity, neonatal immunity, feeback inhibition of B cells
Secreted as monomer important in secondary immune response |
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IgM
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Naive B cell antigen receptor, complement activation
secreted mainly as pentamer low affinity, high avidity |
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antibody idiotype
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refers to the variable region of the antibody, idiotypes refers to antibodies that share the same antigen binding specificity
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antibody isotypes
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refers to the antibody heavy chain types
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epitope
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region on antigen that is recognized by an antibody (or T cell receptor)
can be either conformational or linear |
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idiotope
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region on the antibody that binds antigen
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c-region
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constant region of antibody. consists of 3-4 exons for heavy chains and one exon for light chains. There are different H chain constant regions for different isotypes and are important for antibody effector function
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v-region
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variable region of antibody. consists of V, D, and J gene segments for H chains and V and J for L chains
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V gene segment
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variable gene segment
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D gene segment
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diversity gene segment, unique to H chains
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J gene segment
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joining gene segment
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FRs
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framework regions, areas of the V region that are limited in sequence diversity
important for maintaining the structure of the antibody |
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subclass
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some of the heavy chain isotypes have more than one variant within the same person. ex. IgG has 4 subclasses (IgG1, IgG2, etc)
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L chains
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2 types of light chains, kappa and lambda
60% of B cells express kappa, the rest express lambda only one is expressed per B cell due to allelic exclusion |
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Allelic exclusion
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haplotype exclusion.
phenomenon that B cells usually express only one kind of antibody despite the genetic capacity to express many different antibodies occurs because there is feedback inhibition of V(D)J recombination and because there is a high frequency of errors, making it less likely for a single B cell to have more than one kind of functional H chain or L chain rearrangement |
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3 ways we get antibody diversity
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1. combinatorial diversity
2. Junctional diversity 3. Somatic mutation |
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combinatorial diversity
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diversity achieved by combining different V (D for H chains) and J gene segments and pairing different H and L chains together
happens when hematapoietic stem cell differentiates into B cell |
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Where are the loci encoding H chains and L chains?
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On separate chromosomes
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V(D)J recombination
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1. cleavage step
2. DNA joining step RAG1 and RAG2, and NHEJ enzymes are important for completing the rearrangement generates a coding join and a signal join follows the 12/23 rule |
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12/23 rule
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rearrangements should involve RSSs with dissimilar spacer lengths, which increases the chances that rearrangements using the correct combination of gene segments are used to assemble the V region
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Recombination signal sequence
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conserved heptamer and nonamer separated by 12 or 23-bp spacers, located adjacent to V and J exons or to V, D, and J exons
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how light chains differ from heavy chains
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2 loci for light chains, kappa and lambda
no D segments Kappa light chains can rearrange by deletion or inversion kappa light chains can receptor edit and do so fairly often kappa loci are often deleted in B cells that express lambda |
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which L loci rearranges first, kappa or lambda?
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kappa
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junctional diversity
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addition or deletion of nucleotides at recombination sites
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mechanisms of junctional diversity
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P-addition (RAG)
N-addition (TdT) Exonucleolytic nibbling D segment reading frames |
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P-addition
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RAG mediated resolution of the hairpin intermediate is inexact, so if the cut is not made exactly in the middle of the hairpin, there is an overhang that is filled in, resulting in palindromic DNA sequences
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N-addition
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the enzyme TdT adds DNA bases to the ends (after hairpin cleavage and P-addition)
these are often GC rich most active in Pro-B cells, so mostly seen in H chain rearrangements |
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exonucleolytic nibbling
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When RAG enzymes create DNA break they are repaired by non homologous end joining enzymes (NHEJ). These may trim back the broken DNA ends, and it is most extensive in the D gene segments of H chain rearrangements
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D segment reading frames
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1. Ds can be read in all 3 forward reading frames, as long as junctional modification on both sides make sure they get back to the right reading frame once it joins with the J
2. Ds can rearrange by deletion or inversion (so can read in all 3 reverse frames too) 3. occasionally D-D fusions occur (violation of the 12-23 rule)...common in TCR H chains |
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heavy chain CDR3
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most hypervariable CDR
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Somatic mutation
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occurs only in B cells
occurs after priming during germinal center reactions characteristic of secondary antibody response Stimulated by T cell signals (CD40L and others) directs single nucleotide changes selectively to the heavy chain and light chain variable regions |
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affinity maturation
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when somatic mutation is coupled with selection for antigen binding
mutants with increased affinity for antigen are selected |
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AID enzyme
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activation induced cytidine deaminase
performs somatic mutation and isotype switching |
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How does AID enzyme work
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converts C nucleotides to uridine
DNA repair may then convert to A,T,G, or C could also be converted to A during replication |
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hyper-IgM syndrome
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caused by deficiencies of the AID enzyme
Patients have high levels of unmutated/unswitched antibodies can also be caused by deficiency in CD40L (no signal means no mutation/switching) |
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How does vaccination affect V regions of antibodies
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mutations increase with time after immunization and with repeated immunizations
mutations are clustered in CDRs affinities of antibodies produce increase with more mutations |
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Which has higher levels of junctional diversity, B-cell receptor genes or T cell receptor genes?
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T cell receptor genes, particularly due to D-D fusions
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Is class switching reversible?
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No. It occurs through deletions
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possible consequences of various antibody diversification mechanisms
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autoreactivity
non-productive rearrangements chromosomal translocations |
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What percentage of newly formed BCRs are multireactive, and what happens to them normally B cell development?
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70%
They are censored |
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What type of genetic abnormality do lymphoid malignancies normally have
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translocations in the Ig or TCR loci
translocations lead to over-expression of a cellular growth or survival promoting gene |
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How can you use flow cytometry to check for monoclonal B cell populations?
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use anti-kappa and anti-lambda antibodies on B cells
use flow cytometry to detect when these antibodies bind If the ratio is not 60-40 but closer to 99-1, you have a monoclonal B cell population |
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How can you use PCR to check for monoclonal B cell populations?
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run CDR3 PCR
there will naturally be PCR products of different lengths corresponding to different H chain rearrangements separate PCR products and look at distribution of sizes If there is a spike in the data, you've got a monoclonal B cell population |
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What are the two major mechanisms of allelic exclusion?
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1.there is a low probability of productive rearrangement of the H or L chain, so an even lower probability that a single B cell would have 2
2. feedback inhibition of rearrangement: when a functional protein is made, it transmits a "stop" signal inhibiting further gene rearrangement (shuts off RAG) |
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why do we have allelic exclusion
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fate of B cell depends on reactivity of BCR...if there was more than 1, the lack of specificity would cause the whole system to collapse
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combinatorial diversification mechanism buzzwords
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V(D)J recombination
RAG1 and RAG2 NHEJ enzymes H + L chain pairing B and T cells |
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junctional modifications diversification mechanism buzzwords
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RAG (P-addition)
TdT (N-addition) NHEJ (nibbling) D-D fusions and altered reading frames B and T cells |
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somatic mutation diversification mechanism buzzwords
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AID
co-stimulation by T cells ONLY B cells |
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BCR crosslinking
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IgM (and IgD) are associated with Ig-alpha and Ig-beta molecules, which contain ITAMs in their cytoplasmic tails that mediate signaling functions
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1. Antigen crosslinks 2 IgM molecules
2. Clustering and activation of SSrc-family tyrosine kinases 3. tyrosine phosphorylation of the ITAMs 4. docking of Syk and subsequent tyrosine phosphorylation events 5. signaling cascades activate several transcription factors |
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ITAMs
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Immunoreceptor tyrosine-based activation motif
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Functional responses induced by BCR crosslinking
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increased survival
proliferation Increased expession of B7 Increased expression of cytokine receptors (IL-2, IL-4, BAFF receptors) Increased expression of CCR7 |
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